DRUG RESISTANT EPILEPSY

By

Ahmed Mohammed Fahmy Alharoun

Supervised byProfessor Yasser Metwallywww.yassermetwally.com

Introduction

Considering that epilepsy is one of the mostcommon chronic neurologic disorders, drug-resistant epilepsy is a major public health problem.The consequences of drug-resistant epilepsy can bequite severe, including mortality rates that are 4 to7 times higher in people with drug-resistantseizures.

Introduction

In many patients with epilepsy, seizures are well-controlled with currently available anti-epilepticdrugs (AEDs). However, seizures persist in aconsiderable proportion of these patients. The exactfraction of epilepsy patients who are consideredrefractory varies in the literature, mostly becausethe criteria for classification as pharmaco-resistanthave varied.

Introduction

A substantial proportion (about 30%) of epilepsypatients do not respond to any of two to three firstline AEDs, despite administration in an optimallymonitored regimen.

It is not known why and how epilepsy becomesdrug resistant in some patients while others withseemingly identical seizure types and epilepsysyndromes can achieve seizure control withmedication.

Introduction

Although no single accepted definition exists ofdrug resistant epilepsy, different definitions may beappropriate, depending on the type of seizure andepilepsy syndrome and the purpose for which thedefinition is used. Definitions usually include thenumber of AED failures and the minimal remissionor seizure frequency during a specified duration oftherapy.

Introduction

It is mandatory to exclude false refractoriness relatedto non-epileptic seizures, inadequate AEDs,noncompliance and seizure-precipitating factors.Video-EEG monitoring is an essential tool in thisprocess, aiming to perform a differential diagnosis ofparoxysmal events and a correct classification ofseizures and epileptic syndromes. Non-epilepticevents more frequently found include cardiovascularsyncopes, sleep diseases and psychogenic events.

Introduction

Refractory epilepsy is established when there isinadequate seizure control despite using potentiallyeffective AEDs at tolerable levels for 1-2 years, andexcluding non-epileptic events and poorcompliance.

Introduction

Epidemiologic studies suggest three differentpatterns of drug resistance in epilepsy: de novo,progressive, and waxing-and-waning.

De novo drug resistanceresistance is present from the time of onset of thevery first seizure, before any antiepileptic drug iseven started.

Introduction

Waxing and waning resistanceepilepsy has a waxing and waning pattern: italternates between a remitting (pharmaco-responsive) and relapsing (pharmaco-resistant)course.

Progressive drug resistanceepilepsy is initially controlled but then graduallybecomes refractory. This pattern may be seen, forexample, in childhood epilepsies or in patients withhippocampal sclerosis.

Introduction

In epilepsy, 3 prognostic groups are generallyconsidered: (1) spontaneous remission (20–30%);(2) remission on AEDs (20–30%); (3) persistentseizures under AEDs (30–40%) among whichrefractory epilepsy is included.

Introduction

Factors that have been associated with treatment-resistantepilepsy include:

• Early onset of seizures• Long history of poor seizure control• Having more than one type of seizure• Remote symptomatic etiology (e.g., patients with a

history of brain infection or head trauma)• Certain structural abnormalities (e.g., cortical dysplasia)• Certain abnormalities on electroencephalography (EEG)• History of status epilepticus

Aim of the Work

Our aim is to explore the pathologicalmechanisms underlying drug resistance in epilepsyand to search reviews trying to explain how andwhy drug resistance occurs in some patients withepilepsy to reach better management of thesepatients.

PHARMACORESISTANCE

Pharmacoresistance

Two main hypotheses have been proposed to account forPharmacoresistant epilepsy.

The first hypothesis contends that pharmaco-resistancearises because AEDs do not gain access to their sites ofaction in the brain. This phenomenon is thought to becaused by over-expression of drug efflux transportersat the BBB that limit AED access to the brain.Furthermore, this can also occur in glial and neuronalmembranes, potentially reducing drug efficacy byrestricting access to intracellular target sites. Becauseof the central importance of multidrug transporters, thishypothesis has been designated “transporterhypothesis”.

Pharmacoresistance

The target hypothesis, on the other hand, contendsthat target receptor sites are somehow altered in theepileptic brain so that they are much less sensitiveto the anticonvulsant effects of systemicallyadministered drugs.

Pharmacoresistance

Transporter hypothesis For drugs to enter the brain, they must traverse

either BBB or the blood CSF barrier. Because ofthese anatomical barriers, entry of drugs into thebrain is restricted.

Based on the assumption that penetration of drugsfrom blood into brain and CSF depends mainly onthe drugs’ lipid solubility, drugs required to actwithin the brain, such as AEDs, have generallybeen made lipophilic.

Pharmacoresistance

AEDs penetrate into the CSF by simple diffusion andLipid solubility plays the major role in determining thedifference in rate of entry of AEDs into the brain.

Apart from passive diffusion, drugs may also enter andleave the brain by carrier-mediated transport processes.In this respect, the recent finding of multidrugtransporters of the ABC superfamily, such as P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), in the endothelial cells of theBBB is of particular interest. Furthermore, both P-gpand MRP are expressed in CP epithelial cells that formthe BCB.

Pharmacoresistance

These transporters act as outwardly directed activeefflux mechanisms limiting brain accumulation ofmany lipophilic drugs.

There is accumulating evidence demonstrating thatmultidrug transporters such as P-gp and MRP areover-expressed in capillary endothelial cells andastrocytes in epileptogenic brain tissue surgicallyresected from patients with medically intractableepilepsy.

Pharmacoresistance

Over-expression of efflux transporters in epilepticbrain tissue may be constitutive oracquired/induced, or both mechanisms may be atplay.

Constitutive over-expression could occur as a resultof genetic predisposition, or it could be intrinsic tothe development of the specific pathology.

Pharmacoresistance

Over-expression can be acquired, such as inductionby recurrent seizures or even the AEDs intended toprevent them.

Current preliminary evidence suggests that bothsituations could be taking place.

In addition to intrinsic or acquired over-expressionof multidrug transporters in the BBB or BCB ofpatients with epilepsy, functional polymorphisms ofthese transporters may play a role inpharmacoresistance

Pharmacoresistance

There is increasing evidence that various majorAEDs are substrates for one or more of these effluxcarriers. At least three strategies are used in thisrespect. One is to evaluate whether the brainpenetration of AEDs can be affected by P-gp orMRP inhibitors; a second is to use cell lines thatover-express P-gp or MRPs; and a third is to studydrug penetration into the brain of mdr or mrpknockout mice.

Pharmacoresistance

Verapamil and diltiazem (P-gp inhibitors) increasedthe plasma concentrations of carbamazepine andcaused unacceptable neurotoxicity.

Absence of MRP2 in the BBB led to increasedpenetration of PHT into the brain and significantlyenhanced anticonvulsant activity compared withrats with intact MRP2 function.

Pharmacoresistance

Additional data have shown that a number of otherAEDs including CBZ, Phenobarbital, lamotrigine,gabapentin and topiramate are also substrates for P-gp, MRPs, or both. Hence, it appears that theirover-expression could potentially affect the efficacyof a variety of different AEDs.

Pharmacoresistance

Target hypothesis According to the target hypothesis,

pharmacoresistance occurs when target sites arestructurally and/or functionally modified in such away that they become less sensitive to AEDs.

So far, a reduced sensitivity of drug targets toAEDs in chronic human epilepsy has beensuggested for the voltage-gated Na+ channel andthe GABAA receptor.

Pharmacoresistance

Voltage-gated Na+ channels The target hypothesis is based primarily on studies

with CBZ on voltage-gated sodium channels inhippocampal neurons.

CBZ is known to inhibit voltage-dependent Na+

currents via two classes of mechanisms. It modestlyblocks Na+ channels in their resting state athyperpolarized membrane potentials(voltage dependentblock). In addition, CBZ inhibits Na+ currents in a use-dependent manner; that is, blocking effects are morepronounced when the cell membrane is repetitivelydepolarized at high frequencies.

Pharmacoresistance

In epileptic brain tissue, use dependent block ofNa+ channel activity is absent.

One possibility that can account for an alteredsensitivity of Na+ channels in epileptic tissue maybe that the subunit composition of these channels isaltered, such that the expression of AED-insensitivesubunits or subunit combinations is promoted

Pharmacoresistance

GABAA receptors GABAA receptors mediate the majority of fast

inhibitory neurotransmission in the brain. The major GABAA receptor subtype (60% of all

GABAA receptors) is assembled from the subunitsα1β2γ2. This receptor subtype mediates to a largeextent the anticonvulsant action of BZDs. Whereas,for instance, α4- or α6-containing subunitassemblies are insensitive to BZDs

Pharmacoresistance

Regarding GABAA receptor agonists, reducedactivity of such substances has been described in achronic model of epilepsy.

Combined molecular and functional studiesindicate that a transcriptionally mediated switch inthe alpha subunit composition of GABAA receptorsoccurs in epileptic animals, in particular a decreaseof α1 subunits and an increase of α4 subunits.

These specific changes in drug targets are anattractive concept to explain pharmacoresistance.

Pharmacoresistance

Genetic control of AED targets

It has become clear over the recent years thatseizures cause coordinated and cell-specifictranscriptional changes that result in either an up-or down-regulation of families of ion channelmRNAs. This, in turn, causes alterations in thesubunit composition or density of ion channels,resulting in altered intrinsic and synaptic neuronalproperties.

GROSS PATHOLOGY

Gross pathology

MCDs are increasingly recognized as causes ofepilepsy. The clinical significance and impact ofMCDs are especially high, because MCDs arefrequently associated with pharmacoresistantepilepsy that is refractory to available seizuremedications.

About 40% of children with drug resistant epilepsyharbour a cortical malformation and up to 50% ofthe pediatric epilepsy surgery operations are carriedout in children with an MCD.

Gross pathology

MCDs fall into the following categories: (i)malformations caused by abnormal neuronal andglial proliferation (e.g. hemimegalencephaly, focalcortical dysplasia FCD), (ii) malformations causedby abnormal neuronal migration (e.g. heterotopia,lissencephaly) and (iii) malformations caused byabnormal cortical organization (e.g.polymicrogyria, FCD without balloon cells).

Gross pathology

Focal cortical dysplasia (FCD)

FCD is the single most important cause of focalintractable epilepsy in childhood. It ishistopathologically proved in at least 20% ofpatients in adult epilepsy surgery series and inalmost 50% of children undergoing surgical therapyfor epilepsy.

Gross pathology

Palmini and Luders classification divides FCD intothree major subtypes: mild malformation of corticaldevelopment (mMCD), FCD type I, and FCD typeII. Two further subcategories are recognized withineach of the types: mMCD type I, mMCD type II,FCD type Ia, FCD type Ib, FCD type IIa, and FCDtype IIb.

Gross pathology

FCD usually presents with intractable partialepilepsy, starting at a variable age, but generallybefore the end of adolescence. Since lesions maybe located anywhere in the brain, any type of focalseizure can be observed and focal status epilepticushas been frequently reported. However, infantilespasms may be the first manifestation.

Gross pathology

The term “dual pathology” describes thecoincidence of extrahippocampal temporal lesionsand Ammon’s horn sclerosis.

In presurgical evaluation, the presence of dualpathology must be taken into consideration becauseof the common association between FCD andhippocampal sclerosis.

Gross pathology

In epilepsy caused by FCD, surgical resection is animportant treatment modality. The postoperativerate of FCD patients rendered seizure-free variesfrom about 50% to approximately 65% in majorpatient collectives while reports on thepostoperative outcome of patients with dualpathology are controversial.

Gross pathology

Periventricular nodular heterotopias (PNH) Heterotopias are MCDs characterized by the

presence of apparently normal brain cells inabnormal positions. Three broad categories arerecognized: band heterotopia (double cortex),neuronal heterotopia, nodular heterotopia.

Nodular heterotopia are further divided into:subependymal heterotopia (subsumingperiventricular nodular heterotopia), andsubcortical heterotopia.

Gross pathology

PNH is among the most common MCDs and affectedpatients are frequently characterized by focal drug-resistant epilepsy.

Wide variety of clinical pictures are often present.Epilepsy can begin in the second or third decade of lifeor earlier, with seizures ranging from rare to veryfrequent, often resistant to polytherapy. Most patientspresent with partial seizures. Mental retardation,usually absent or mild, can also be severe andassociated with neurological deficits and dysmorphicfeatures.

Gross pathology

Tuberous sclerosis complex (TSC) Tuberous sclerosis or tuberous sclerosis complex

(TSC) is a multisystemic disorder involvingprimarily the central nervous system, the skin, andthe kidney. A prevalence of 1:30 000 – 50 000 hasbeen reported. In the brain, the characteristicfeatures are cortical tubers, subependymal nodulesand giant cell tumors. Cortical tubers are moredirectly related to epileptogenesis.

Gross pathology

TSC is transmitted as an autosomal dominant trait,with variable expression seen within families.

Epileptic seizures are frequent in TSC. Theyusually begin before the age of 15, mostly in thefirst 2 years of life. Infantile spasms are the mostcommon manifestation of epilepsy in the first yearof life, sometimes preceded by partial seizures.

Gross pathology

Glioneuronal tumors (GNTs) Long-term epilepsy associated glioneuronal

tumours (GNTs) mainly comprise gangliogliomas(GGs) and dysembryoplastic neuroepithelialtumours (DNTs).

Both neoplasms are rare, with an incidence ofapproximately 1.3% of all brain tumours.

Any lobe can be affected, but temporal lobelocations appear to be far more frequent for bothGGs and DNTs.

Gross pathology

Clinical presentation is with drug resistant partialepilepsy. In a population of 89 patients with DNTs,partial seizures were the first clinical signs in 75%,while only 9% had neurological deficits consistingof quadranopsia. Epilepsy started at a mean age ofnine years (range 1-20 years) and proved resistantto different antiepileptic medications.

The large majority of patients with GNTs becameseizure free after surgical resection.

Gross pathology

Do seizures start within the lesion or theperilesional region?

The high success rate of “lesionectomy” duringepilepsy surgery, with many studies reporting over a60– 75% seizure-free rate, supports the idea that thelesions directly produce seizures.

However, this still leaves a substantial minority ofpatients that continue to have seizures followinglesionectomy, suggesting that the epileptogenic zonewas not contained within the lesion in those cases.

Gross pathology

Is epileptogenesis primarily a result ofcircuit abnormalities or cellular/moleculardefects?

Epileptogenesis in MCDs is primarily due to circuitabnormalities or cellular and molecular defects.

Circuit abnormalities (the epileptic circuit) mightconsist of aberrant connectivity of neurons that arecompletely normal in function, whereascellular/molecular mechanisms (the epileptic neuron)would involve a defect involving intrinsic neuronalfunction in the context of normally wired and fullyoperational circuits.

Gross pathology

Ultimately, both network and cellular/molecularabnormalities will stimulate epileptogenesis byupsetting the normal physiological balance betweenexcitation and inhibition in the brain.

Gross pathology

Expression of drug transporters in pathologicallesions associated with refractory epilepsy

When determining P-gp and MRP1 expression in threecommon causes of refractory epilepsy, namelydysembryoplastic neuroepithelial tumors (DNTs) ,focal cortical dysplasia (FCD), and hippocampalsclerosis, there was over-expression of both P-gp andMRP1 in reactive astrocytes in the epileptogenic tissuein all three conditions, and MRP1 over-expression indysplastic neurons in FCD.

MANAGEMENT

Management

Evaluating patients with suspected pharmacoresistantepilepsy demands a systematic and holistic approachwith equal emphasis on quality of life and psychosocialand cognitive factors.

The clinical assessment should be based on thefollowing principles:Review and confirm the diagnosisof epilepsy, Identify the cause and type of seizure,Review past and present medications, Chooseantiepileptic drugs, Discuss issues such as seizureprecautions and lifestyle modifications.

Management

AEDs

In chronic epilepsy (more than 5 years), theaddition of a new AED provided a seizure freedomof 17% and a 50–99% seizure reduction of 25%.

Management

Epilepsy surgery Resective surgery is based on removal of the entire epileptogenic area without

causing a permanent neurological deficit. The localization of the epileptogeniczone in focal epilepsy is typically based on seizure semiology, interictal and ictalEEG findings, as well as SPECT and MRI lesions.

Curative procedures: Anterior temporal lobectomy and hippocampectomy: for mesial

temporal lobe epilepsy associated with hippocampal sclerosis Lesionectomy and lobectomy: targeting seizure foci outside the temporal

lobe Multilobar resections and hemispherectomy: when seizures arise from

extensive, diffuse, or multiple regions of a single hemisphere. whenseizures arise from extensive, diffuse, or multiple regions of a singlehemisphere.

Management Palliative procedures: Corpus callosotomy: by disconnecting the two

hemispheres, this procedure aims to hinder the fastinterhemispheric spread of seizure discharges.Callosotomy may be complete or involve only aportion of the corpus callosum.

Multiple subpial transections: for seizures arisingfrom eloquent cortex (ie, from areas that cannot beremoved without causing unacceptable neurologicdeficits). Therefore, the surgeon only transects theepileptogenic cortex in a vertical manner, so as tointerrupt the horizontal cortical connections withoutresection.

Management

Ketogenic diet ketogenic diet is mainly used in pediatric patients (due to

tolerability) as second line treatment in focal nonsurgicalrefractory and generalized symptomatic epilepsy.

It is a strict regimen, high in fat and low in carbohydrateand protein (typically in a ratio of 4:1 or 3:1)

A recent randomized controlled trial showed a reduction inseizure frequency more than 50% in 38% of children withdrug-resistant epilepsy.

Such a strict regimen is difficult to implement and maintainand requires close supervision by a dietician and physician.

Management

Vagus nerve stimulation It is a nonpharmacologic alternative for adults and

adolescents over age 12 years who have intractablefocal seizures and are not favorable surgicalcandidates.

At least one-third of patients who receive this treatmentshow a sustained response, defined as a 50% or greaterreduction in seizures.

However, few achieve freedom from seizures, andtherefore this therapy is considered palliative and isreserved for patients who are not candidates for surgeryor for whom surgery has failed.

Management

Treatments under investigation Local drug delivery: Polymers containing AEDs consist

of 2- to 3-mm microspheres that might be placed near theepileptogenic zone.

Targeted electrical stimulation: Direct stimulation: targets presumed epileptogenic brain

tissue such as the neocortex or hippocampus. Indirect stimulation: targets presumed seizure-gating

networks such as in the cerebellum and various deep brainnuclei in the basal ganglia or thalamus (deep brainstimulation), which are believed to play a central role inmodulating the synchronization and propagation of seizureactivity.

Management

Cell and gene therapies Bioengineered cells capable of delivering

anticonvulsant compounds might be transplantedinto specific areas of the brain.

Delivering genes by viral vectors to induce thelocalized production of antiepileptic compounds insitu.

Cell transplantation is aimed at restoring thephysiologic balance of neurotransmitters.

Recommendations

Future directions of research and experimental studies shouldaddress revealing more data about the following

Evidence that the multidrug transporters regulate intraparenchymalconcentrations of AEDs.

Evidence that multidrug transporter expression and/or transporterfunction is upregulated in human and experimental epilepsy.

Regarding drug targets, evidence should be available that drugtargets are less sensitive to a given AED in chronic epilepsy.

Evidence that genetic or pharmacological manipulation of drugtransporters/drug targets affects sensitivity to AEDs.

In addition, data on human epilepsy patients should be obtainedregarding association of polymorphisms in drug transporter/drugtarget genes with clinical pharmacoresistance.

The end

Thank you